Adrenergic dysregulation (hyperadrenergia or hypoadrenergia) refers to abnormal neuronal activation or secretion of the hormone adrenaline and/or the neurotransmitter noradrenaline. Adrenergic dysregulation may occur at both baseline levels of stimulation and in response to external stress. Excessive adrenergic stimulation results in symptoms such as high blood pressure, hyperactivity, physical aggression, motor tics, and insomnia.
Effective drug therapies require control of blood serum levels of drug. Time release hydrophilic matrices are known in the field of drug formulations. For example, one such hydrophilic matrix is hydroxypropyl methylcellulose (HPMC). HPMC matrixes in a surrounding medium of low ionic strength with electrolytes typically hydrate to produce an intact gel layer. An intact gel layer may provide predictable release of an incorporated drug from the matrix by migration through the gel layer. However, at intermediate ionic strengths, the same matrix may lose shape and disintegrate rapidly. Thus, electrolytes present in the surrounding medium may modify the release profile of drugs from HPMC matrices. Modification of the release profile of a drug resulting from differences in matrix environment may be detrimental to the therapeutic usefulness of a drug.
Drugs themselves may also influence the rate of hydration and the rate of gelation of hydrophilic matrixes. (Mitchell, et al., Int. J. Pharm. (1993) 100: 165-173). Therefore, the incorporation of drugs in hydrophilic matrices may result in unpredictable dissolution profiles, which may result in unpredictable therapeutic efficiency of the dosage forms.
Drug release from an oral solid extended release dosage form and subsequent absorption of the drug from the gastro-intestinal tract into the blood stream is dissolution-rate dependent and may be slow and irregular especially in the case of sparingly water soluble, slightly water soluble, very slightly water soluble, practically water insoluble, or a water insoluble drug, as defined according to the United States Pharmacopeia 24, p 10.
Additives may be added to hydrophilic matrixes to modify the gelling rate and/or the release rate of an incorporated drug. However, the nature of the interaction of a particular drug with the matrix and additive is not generally predictable. This is particularly problematic for drugs administered in low dosages or drugs with limited solubility. It is also difficult to correlate the release rate of a drug with its serum or blood concentration when complex matrix/additive systems are used.
The traditional oral dosage formulations of α2-adrenergic receptor agonists have disadvantages. The release profile of the traditional oral dose is typically a rapid and bolus release followed by rapid and complete absorption. For example, the traditional oral formulation of clonidine has side-effects including sedation about an hour after the given dose, when the patient may become transiently sedated or fall asleep. Because of the rapid absorption of the drug, the half-life of this dosage form of clonidine is essentially the same as the biological half-life of about four to six hours. Thus, in the traditional formulation of clonidine, the therapeutic effect may wear off too soon and possibly be accompanied with rebound hyperarousal. This may occur in the middle of the night causing insomnia and nightmares. Such side effects have limited the practical usefulness of orally administered clonidine. Despite the usefulness of clonidine in the treatment of hypertension, the regimen of administration required by the pharmacokinetic profile of the drug resulted in quite wide fluctuations in plasma concentrations, even at steady state. (Fujimura A., et al., J. Clin. Pharmacol. 1994; 34:260-265). It has been shown that many of the adverse events (AEs) observed during oral clonidine administration were related to its high peak plasma concentrations. (Lowenthal D T., J. Cardiovasc. Pharmacol., 1980; 2(suppl.):S29-S37).
The pharmacokinetic profile and relationship between plasma levels and AEs necessitate frequent dosing and result in a “roller coaster” effect characterized by “peak” AE of sedation and trough AE of rebound hypertension. In an effort to address the “roller coaster” issue, a 7-day patch formulation for clonidine (marketed under the brand name Catapres-TTS) was developed. Early studies showed that transdermal administration of clonidine was safe and effective in controlling hypertension (Weber, M A, et al., Arch. Intern. Med., 1984; 144(6):1211-1213. In addition, these studies suggested a milder AE profile for the patch formulation than for oral clonidine with reduced sedation and lack of rebound hypertension. The patch, however, had severe limitations. First, localized skin reactions such as erythema, pruritus and localized vesiculation was observed in over 50% of patients. In a large database of exposure to transdermal clonidine reviewed by the FDA, these skin reactions led to discontinuation of treatment in 19% of patients. Furthermore, the label cautions that in patients who develop an allergic reaction to transdermal clonidine, substitution of oral clonidine may also elicit an allergic reaction including generalized rash, urticaria or angioedema. Another problem that has plagued the patch is poor adhesiveness necessitating the use of an adhesive overlay.
A capsule containing microcapsule having a range of differing release profiles has been used as a sustained release formulation of clonidine. (Mancia, G. et al., J. Cardiovasc. Pharmacol., 1981; 3:1193-1202; Fyhrquist, F., Intl. J. Clin. Pharmacol., Therapy and Toxicol., 1983; 21:12:634-636). This formulation is known as Catapresan-Perlonget and is available in Europe. Typically, the sustained release formulation contains different membrane coated nuclei of the drug. One nuclei releases the drug rapidly while the others release more slowly over 3 or 6 hours, respectively. (Mancia).
For the foregoing reasons, there is a need for drug formulations, such as low dosage drug formulations, that are capable of stable therapeutic dosage profiles by providing an extended serum level concentration of active for an extended period in order to avoid possible “peak and trough” side effects (effectiveness at peak serum levels and rebound exacerbation of symptoms at trough levels).